Direct GDP-KRASG12C inhibitors and mechanisms of resistance: the tip of the iceberg

Joshua C Rosen; Adrian Sacher; Ming-Sound Tsao

doi:10.1177/17588359231160141

Direct GDP-KRAS^G12C inhibitors and mechanisms of resistance: the tip of the iceberg

Ther Adv Med Oncol. 2023 Mar 16:15:17588359231160141. doi: 10.1177/17588359231160141. eCollection 2023.

Authors

Joshua C Rosen^{1

2}, Adrian Sacher^{1

3

4}, Ming-Sound Tsao^{5

2

6}

Affiliations

¹ Princess Margaret Hospital Cancer Centre, University Health Network, Toronto, ON, Canada.
² Department of Laboratory Medicine and Pathobiology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
³ Division of Medical Oncology, Department of Medicine, Princess Margaret Cancer Centre, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
⁴ Department of Immunology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
⁵ Princess Margaret Hospital Cancer Centre, University Health Network, 101 College Street, Toronto, ON M5G1L7, Canada.
⁶ Department of Medical Biophysics, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada.

Abstract

Kirsten rat sarcoma viral oncogene homolog mutations are observed in 25% of lung adenocarcinoma and 40% of these are G12C mutations. Historically, no approved targeted agents were available for patients with any KRAS mutation, and response rates to standard-of-care therapies were suboptimal. Newly developed inhibitors directed toward KRAS^G12C have been successful in clinical trials with overall response rates ranging between 32% and 46%, and two FDA approvals were granted in May 2021 and December 2022 as second-line or later monotherapies. However, rapid tumor resistance complicates their use as a monotherapy. With the rapid development of this novel class of inhibitors, it is important to discern the different types of tumor resistance that may arise and how each can differently contribute to tumor growth and survival. G12C inhibitor resistance is under investigation and combinations of therapies with G12C inhibitors have been proposed. Much of this insight is gleaned from preclinical investigations, as our knowledge of clinical resistance is in its infancy. In this review, we summarize the preclinical development of KRAS^G12C inhibitors, their clinical evaluations, different types of resistance mechanisms to these compounds, and ways of overcoming them. Finally, we underscore the importance of basic and translational investigations of these molecules in a landscape where their clinical evaluations garner the most attention, and we set the stage for what is to come.

Keywords: G12C; KRAS; clinical trial; drug resistance; preclinical; targeted therapy.

Publication types

Review